BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels
BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels
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DOI：
10.1093/hmg/ddg069
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发表时间：
2003-03-15
影响因子：
3.5
通讯作者：
Eng, C
中科院分区：
文献类型：
--
作者：
Waite, KA;Eng, C
肿瘤抑制基因PTEN编码双特异性磷酸酶，其识别蛋白质和磷脂酰肌醇底物并调节细胞功能，如迁移和增殖。已显示PTEN的生殖系突变引起Cowden综合征、Bannayar-Riley-Ruvalcaba综合征和Proteus综合征。最近，在罕见的Cowden综合征家系中发现了编码骨形态发生蛋白（BMP）1A型受体的基因BMPR 1A的种系突变，这表明BMP信号传导与PTEN之间可能存在联系。因此，我们试图确定BMP 2刺激是否改变乳腺癌细胞系MCF-7中的PTEN蛋白水平。我们发现暴露于BMP 2以时间和剂量依赖性方式增加PTEN蛋白水平。PTEN蛋白的增加是快速的，并且不是由于新蛋白合成的增加，因为放线菌酮处理不抑制BM 132诱导的PTEN积累，表明BMP 2刺激抑制了PTEN蛋白降解。事实上，我们发现BMP 2处理MCF-7细胞减少了PTEN与降解途径中的两种蛋白质UbCH 7和UbC 9的结合。这些数据表明，BMP 2暴露可以通过降低PTEN与降解途径的关联来调节PTEN蛋白水平。这开辟了一种调节PTEN活性的新模式，有待进一步研究，并可能解释为什么BMPR 1A可以作为PTEN突变阴性考登综合征的次要易感基因。
The tumour suppressor gene PTEN encodes a dual-specificity phosphatase that recognizes protein and phosphatidylinositiol substrates and modulates cellular functions such as migration and proliferation. Germline mutations of PTEN have been shown to cause Cowden syndrome, Bannayar-Riley-Ruvalcaba syndrome and Proteus syndrome. Recently, germline mutations in BMPR1A, the gene encoding the type 1A receptor of bone morphogenetic proteins (BMP) have been found in rare families with Cowden syndrome, suggesting that there may be a link between BMP signaling and PTEN. We thus sought to determine whether BMP2 stimulation alters PTEN protein levels in the breast cancer line, MCF-7. We found that exposure to BMP2 increased PTEN protein levels in a time- and dose-dependent manner. The increase in PTEN protein was rapid and was not due to an increase in new protein synthesis, as cycloheximide treatment did not inhibit BM132-induced PTEN accumulation, suggesting that BMP2 stimulation inhibited PTEN protein degradation. Indeed, we found that BMP2 treatment of MCF-7 cells decreased the association of PTEN with two proteins in the degradative pathway, UbCH7 and UbC9. These data indicate that BMP2 exposure can regulate PTEN protein levels by decreasing PTEN's association with the degradative pathway. This opens up a new mode of regulating PTEN activity to be investigated further and may explain why BMPR1A can act as a minor susceptibility gene for PTEN mutation negative Cowden syndrome.